intravaginal rings for continuous low-dose administration
TRANSCRIPT
Intravaginal rings for continuous low-dose administration of cervicalripening agents
Wang, Y., Boyd, P., Hunter, A., & Malcolm, R. K. (2018). Intravaginal rings for continuous low-doseadministration of cervical ripening agents. International Journal of Pharmaceutics, 549, 124–132.https://doi.org/10.1016/j.ijpharm.2018.07.053
Published in:International Journal of Pharmaceutics
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Download date:16. Nov. 2021
1
Intravaginal rings for continuous low-dose 1
administration of cervical ripening agents 2
3
Yujing Wang1, Peter Boyd1, Alyson Hunter2, R. Karl Malcolm1* 4
5
1School of Pharmacy, Queen’s University Belfast, Belfast BT9 7BL, UK; 6
2Royal Jubilee Maternity Service, Belfast Health and Social Care Trust, Belfast BT12 7
6BA, UK 8
*Corresponding author. Tel: +44 (0)28 9097 2319; E-mail: [email protected] 9
2
Abstract 10
Intravaginal rings (VRs) have been widely reported for administration of pharmaceutical 11
drugs – most notably estrogens, progestogens and antiretrovirals – to the vagina for clinical 12
benefit. Here, for the first time, we describe the design, manufacture and preclinical testing 13
of VRs for sustained/controlled release of the cervical ripening agents isosorbide 14
mononitrate (ISMN) and misoprostol (MP), either singly or in combination. Matrix-type 15
silicone elastomer VRs containing ISMN showed declining daily release rates, ranging 16
from 31–168 mg (Day 1) to 3–25 mg (Day 11). Novel orifice-type rings, in which a MP-17
containing silicone elastomer core is partially exposed to the external environment by 18
overmolding with a non-medicated silicone elastomer sheath containing orifices, provided 19
relatively constant daily MP release rates over 14 days (~20 or 60 μg/day depending on the 20
formulation type). Combination vaginal rings offered simultaneous release of both ISMN 21
and MP over 14 days, with an almost constant MP release rate (60 μg/day) and steadily 22
declining daily ISMN release (295 mg on Day 1 and 24 mg on Day 11). The VR design 23
can be readily tailored to provide sustained or controlled release of ISMN and MP at rates 24
potentially useful for cervical ripening. 25
26
Keywords 27
induction of labour; silicone elastomer drug delivery device; vaginal drug administration; 28
controlled release; sustained release; out-patient. 29
30
3
1. Introduction 31
Flexible polymeric ring-shaped devices have been investigated since the 1970s for sustained 32
or controlled release of drug substances to the human vagina. To date, six vaginal ring (VR) 33
products have reached market, each offering release of one or more steroid molecules for 34
estrogen replacement therapy (Estring® and Femring®), contraception (Nuvaring®, 35
Progering® and Ornibel®) or hormone supplementation and pregnancy maintenance during in 36
vitro fertilization (Fertiring®) (Brache et al., 2013; Friend, 2011; Malcolm et al., 2015, 2012). 37
Since 2002, great progress has been made in the design and development of various 38
antiretroviral-releasing VRs for reducing HIV acquisition (Kiser et al., 2012; Malcolm et al., 39
2015, 2010; Thurman et al., 2013), with a dapivirine-releasing silicone elastomer ring having 40
recently completed late-stage clinical testing and currently under regulatory review by the 41
European Medicines Agency (Baeten et al., 2016; Devlin et al., 2013; Nel et al., 2016b). A 42
major impetus for continued innovation in VR design has been the growing interest in 43
combination HIV microbicide and multipurpose prevention technology products for which 44
release needs to be individually tailored for each drug molecule (Baum et al., 2012; Boyd et 45
al., 2016; Derby et al., 2017; Fetherston et al., 2013; Friend et al., 2013; Malcolm et al., 2015, 46
2014; Moss et al., 2016; Murphy et al., 2014; Smith et al., 2017; Shweta R. Ugaonkar et al., 47
2015; Shweta R Ugaonkar et al., 2015). However, other clinical indications within women’s 48
health are also likely to benefit from enhanced drug administration using existing or new VR 49
technologies. 50
51
Induction of labour (IOL) is a widely-used practice in obstetrics to prevent maternal and fetal 52
morbidity and mortality. However, a major complication of IOL is hyperstimulation of the 53
4
uterus, which can lead to the sudden onset of powerful, frequent and painful contractions 54
which women may find unbearable or frightening. These uterine contractions can damage the 55
fetus due to hypoxia as the placenta cannot be fully revascularised if the uterus is contracting 56
too frequently. Despite these concerns, there is increasing demand to deliver IOL in an 57
outpatient setting where women can be more comfortable and relaxed and reduce their length 58
of stay in hospital. Here, we describe a potential new IOL method involving slow and 59
continuous administration of cervical ripening agents from VRs. This approach has the 60
potential to more closely mimic the natural cervical ripening process and spontaneous onset 61
of labour and reduce the incidence of hyperstimulation, making it safer and more acceptable 62
to women, particularly in an out-patient setting. 63
64
Cervicovaginal administration of pharmacological agents – most notably dinoprostone and 65
misoprostol – has been widely used to ripen the cervix as a method for initiating IOL (Agarwal 66
et al., 2012; Alfirevic et al., 2015; Calder et al., 2008; MacKenzie, 2006; Vogel et al., 2017; 67
Zhang et al., 2015). Two forms of vaginal dinoprostone are already used routinely. Prepidil® 68
is a non-aqueous gel containing 0.5 mg dinoprostone in 3 g triacetin which is administered to 69
the endocervix every 6 h up to a maximum of three doses in 24 h. Cervidil®/Propress® is a 70
pessary-type dosage form comprising 10 mg dinoprostone dispersed within a hydrogel 71
copolymer inserted in a mesh pouch. The insert is placed in the posterior fornix of the vagina 72
and provides sustained release of dinoprostone over 12 h, after which the pouch is removed. 73
Thus, use of modified release formulations for cervical ripening is already well established 74
and offers certain advantages over more conventional immediate-release products (Embrey et 75
al., 1980; Lyrenäs et al., 2001). 76
5
77
Vaginal administration of the synthetic prostaglandin misoprostol, often in the form of 78
fractionated tablet doses (25 µg) of the anti-ulcer product Cytotec®, has also been widely 79
reported for cervical ripening (Furukan et al., 2007; Rodrigues et al., 1998; Sanchez-Ramos 80
et al., 1998; Sharma et al., 2005; Zieman et al., 1997). As with dinoprostone, a hydrogel insert 81
for sustained-release vaginal administration of misoprostol has also been developed, marketed 82
under the brand names Mysodelle®/Myspess®/Misodel® and offering administration rates of 83
approximately 7 g/h misoprostol (Miller et al., 2016; Powers et al., 2008; Stephenson and 84
Wing, 2015; Wing, 2008; Wing et al., 2013). 85
86
Although more commonly used for the treatment of angina pectoris, there has also been 87
interest in the use of the nitric oxide donor isosorbide mononitrate (ISMN) for cervical 88
ripening (Agarwal et al., 2014, 2012; Bollapragada et al., 2009; Bullarbo et al., 2007; 89
Chanrachakul et al., 2002, 2000; Chwalisz et al., 1997; Habib et al., 2008; Ledingham et al., 90
2000; Norman, 1996; Tschugguel et al., 1999; Väisänen-Tommiska et al., 2003). In contrast 91
to prostaglandins, nitric oxide donors induce cervical ripening without causing uterine 92
contractions, making them particularly interesting for use in out-patient settings where fetal 93
monitoring is not possible. 94
95
Here, for the first time, we report that silicone elastomer VRs can offer sustained/controlled 96
release of misoprostol and ISMN at rates likely to be clinically effective for cervical ripening 97
(Amorosa and Stone, 2015; Leopold and Sciscione, 2017; Sharp et al., 2016). A combination 98
6
VR device offering release of both agents at significantly different release rates is also 99
described. 100
2. Materials and methods 101
2.1. Materials 102
ISMN (70% w/w in lactose) and pure ISMN (98%) were purchased from Clariant (Leeds, UK) 103
and iChemical Technologies Inc. (Shanghai, China), respectively. Misoprostol (MP, 1% w/w 104
dispersion in HPMC) was purchased from Sequoia Research Products Ltd. (Pangbourne, UK). 105
DDU-4320 silicone elastomer kits were purchased from NuSil Technology LLC (Carpinteria, 106
CA, US). HPLC-grade acetonitrile, HPLC-grade acetone, sodium chloride, potassium 107
hydroxide, calcium hydroxide, bovine serum albumin, lactic acid, acetic acid and glucose 108
were bought from Sigma (Gillingham, UK). Urea and hydrogen chloride (37% w/w in water) 109
were obtained from VWR International Ltd. (Dublin, Ireland). Millipore Direct-Q 3 UV 110
Ultrapure Water System (Watford, UK) was used to obtain HPLC-grade water. 111
2.2. Manufacture of vaginal rings 112
Silicone elastomer matrix-type VRs (Fig. 1A) containing various loadings of ISMN (100, 500 113
and 1000 mg per ring) were manufactured on a laboratory-scale injection molding machine, 114
according to well-established and previously reported manufacturing protocols (Boyd et al., 115
2016; Fetherston et al., 2013). Briefly, the required amounts of ISMN were added to both 116
Parts A and B of the MED-4320 addition-cure silicone elastomer system contained in custom 117
screw-cap polypropylene containers, and the contents of each container individually mixed 118
using a Dual Asymmetric Centrifuge (DAC) mixer (SpeedMixerTM DAC 150 FVZ-K, 119
Hauschild, Germany) for 30 s at 3000 rpm. The Part A and B premixes were combined in a 120
7
1:1 ratio in a polypropylene container, hand-mixed using a spatula, and then speedmixed (30 121
s, 3000 rpm) to produce the active silicone elastomer mixture. The active mix was manually 122
injected into a heated (60 °C) matrix ring mold assembly fitted to the molding machine using 123
a SEMCO® injection cartridge and cured for 10 min producing matrix-type rings (dimensions: 124
7.6 mm cross-sectional diameter and 55.0 mm external diameter). 125
126
Silicone elastomer reservoir-type VRs (Fig. 1B) – comprising ISMN (7% w/w) or MP (0.2% 127
w/w) in a central core, with the core encapsulated with a silicone elastomer sheath – were 128
similarly manufactured by injection molding via a previously described three-step process 129
(Boyd et al., 2016). Briefly, active silicone elastomer mixtures, prepared as described for the 130
matrix-type rings, were injected into a core ring mold assembly (Fig. 1D) and cured at 60 oC 131
for 10 min to produce ISMN-loaded cores with 4.5 mm cross-section diameter and 51.9 mm 132
external diameter. Full-length or half-length cores were then placed in a custom mold 133
assembly and overmolded with non-medicated MED-4320 silicone elastomer in two (top and 134
bottom) additional injection molding steps. The resulting reservoir-type rings had the 135
following dimensions: 4.5 mm core diameter, 7.6 mm cross-sectional diameter, 55.0 mm 136
external diameter and 1.55 mm membrane thickness. 137
138
Silicone elastomer orifice-type VRs (Fig. 1C) – comprising ISMN or MP in a central silicone 139
elastomer core and partially encapsulated with a silicone elastomer sheath containing various 140
orifices exposing the underlying core – were manufactured in a similar manner to reservoir 141
rings except using custom-designed injection molds with pins designed to partially expose the 142
8
drug-loaded central core to the external environment via orifices in the membrane (Figure 1E, 143
1). 144
2.3. Differential scanning calorimetry 145
Thermal analysis of ISMN, MP and samples taken from the drug-loaded rings was performed 146
using differential scanning calorimetry (DSC; TA Instruments Q100; 50 mL min-1 nitrogen 147
flow; –70 oC to 150 oC at a rate of 10 oC min-1) to probe the nature of the drugs within the 148
rings, following established methods (Boyd et al., 2016; Fetherston et al., 2013). 149
2.4. Quantification of ISMN in the rings 150
Individual VRs were cut into 2 mm slices and placed in a 250 mL glass bottle (Duran GLS 151
80) containing 100 mL acetone. The bottles were placed in a shaking orbital incubator (Infors 152
HT Unitron, Switzerland; 37 oC, 60 rpm, 25 mm orbital throw). After 7 d, the supernatants 153
were collected and diluted 20-fold with water-acetonitrile (90:10, v/v). The amount of ISMN 154
in each VR was analysed by ultra-performance liquid chromatography (UPLC). 155
2.5. In vitro release testing 156
Individual VRs were placed into 250 mL glass bottles (Duran GLS 80) containing 50 mL 157
pH 4.2 simulated vaginal fluid (SVF). SVF mimics the chemical composition of vaginal fluid 158
(Owen and Katz, 1999). The bottles were placed in the shaking orbital incubator (Infors HT 159
Unitron, Switzerland; 37 oC, 60 rpm, 25 mm orbital throw) for 14 days. Sampling (1 mL) 160
followed by complete replacement of the release medium was performed daily except on 161
Fridays when the flask was refilled with 100 mL SVF and no sampling was performed again 162
until the following Monday. The amount of drug in each sample was quantified by UPLC, 163
9
and the data used to construct release vs time plots. All release testing experiments were 164
conducted n=4. 165
2.6. Quantification of ISMN and MP using UPLC 166
ISMN and MP were quantified using a Waters ACQUITY UPLC system fitted with an 167
ACQUITY UPLC BEH C18 column (2.1 50 mm, 1.7 m) and an in-line filter (0.2 m). 168
ISMN samples were injected (1.0 L) onto the column (40 oC) and isocratic elution was 169
performed with a mobile phase of water-acetonitrile (90/10, v/v) at flow rate of 0.6 mL/min. 170
ISMN was detected at 210 nm with a 0.76 min retention time. MP samples were injected (2.0 171
L) onto the column (40 oC) and isocratic elution was performed using a water-acetonitrile 172
(50/50, v/v) mobile phase at 0.6 mL/min flow rate. MP was detected at 210 nm with a 0.69 173
min retention time. Linear ranges for ISMN and MP were 25–800 g/mL and 0.5–25 g/mL, 174
respectively. 175
2.7. Statistical analyses 176
Statistical analyses were performed using one-way ANOVA, followed by post-hoc analysis 177
using the Tukey-Kramer multiple comparisons test. Statistical significance is defined as p < 178
0.05. Analysis was conducted using GraphPad Prism. 179
3. Results 180
3.1. Design and manufacture of rings 181
Matrix-type rings containing ISMN (F1–F4, Table 1), reservoir and orifice-type rings 182
containing ISMN (F5–F8, Table 1), and matrix-type and orifice-type rings containing MP 183
(F9–F13, Table 1) were manufactured successfully; Fig. 2 shows representative photographs. 184
10
The different ring designs are intended to offer different drug release rates. Matrix-type rings 185
contain the drug distributed uniformly throughout the entire volume of the ring (Fig. 1A), and 186
typically exhibit declining release rates with time (Boyd et al., 2016; Fetherston et al., 2013; 187
Malcolm et al., 2016). Reservoir rings contain a drug-loaded core and a non-medicated 188
membrane (Fig. 1B) that controls the drug release rate from the core via a permeation 189
mechanism, and typically results in constant release rates (Boyd et al., 2016; Malcolm et al., 190
2016, 2005). Orifice-type rings (Fig. 1C) – reported here for the first time – are similar in 191
construction to reservoir-type rings except that the core containing the drug active(s) is 192
partially exposed to the external environment by orifices extending through the rate-193
controlling membrane, intended to further modulate the drug release rate. 194
3.2. Thermal analysis of rings 195
DSC analysis was performed to investigate the physical state of the drugs within the rings, 196
since this impacts the release mechanism. The thermograms of the non-medicated silicone 197
elastomer sample and each of the representative ring formulations F1, F2, F3, F6, and F8 (Fig. 198
3A) show an endothermic peak close to –45oC, due to crystalline melting of the silicone 199
elastomer. Ring samples F1, F2, F3 and F6 show an additional endothermic peak at ~90°C, 200
attributed to melting of crystalline ISMN. Thus, these ring devices are shown to contain solid 201
crystalline ISMN (i.e. the drug is incorporated above its solubility limit in the silicone 202
elastomer). The peak size associated with the ISMN melting transition correlates with the 203
ISMN loading in the ring. Melting enthalpies associated with the ISMN were linearly 204
correlated with the mass fraction of ISMN in the rings (Fig. 3B). From the x-intercept of the 205
fitted line, the solubility of ISMN at its melting point in the silicone elastomer ring was 206
determined to be 0.62% w/w (Gramaglia et al., 2005; Woolfson et al., 2003). This is important, 207
11
as diffusion of drugs through silicone elastomers (and therefore release of drugs from VRs) 208
requires at least some of the incorporated drug to be in the dissolved state (Malcolm et al., 209
2003, 2016). 210
211
No discernible thermal transition related to crystalline melting of MP was observed for either 212
the supplied MP material (a 1% dispersion in HPMC) or the ring loaded with 0.2% w/w MP 213
(F8, Table 1, Fig. 3A). This is due to the very low concentration of MP in the supplied 214
material, which is significantly below the DSC detection limit. However, a very broad 215
endothermic peak (30–130 oC) was observed for MP (1% in HPMC) (Fig. 3A), due to 216
dehydration of HPMC during heating (Chandak and Verma, 2008). This broad peak was 217
greatly suppressed in the thermogram of the MP-containing ring (F8) due to dilution of the 218
MP material within the silicone elastomer. 219
3.3. Release of ISMN from VRs 220
ISMN was effectively released from matrix-type rings F1–F4 into the SVF release medium, 221
displaying typical ‘burst and decline’ release profiles (Fig. 4A). Release rates were dependent 222
on the initial ISMN loading in the rings, with Day 1 values ranging between 31 and 168 mg. 223
By Day 4, the daily quantities of ISMN released from the rings had declined to between 8–57 224
mg, and to 3–25 mg by Day 11. These daily release quantities administered from the rings are 225
of an entirely similar order of magnitude to doses reported previously for vaginal 226
administration of ISMN tablets in both out-patient and in-patient settings (Agarwal et al., 227
2014, 2012; Bollapragada et al., 2009; Bullarbo et al., 2007; Chanrachakul et al., 2002; Habib 228
et al., 2008; Vidanagamage and Goonewardene, 2011). The continuous dosing of ISMN 229
offered by the rings may be clinically more effective and enhance compliance compared to 230
12
the periodic dosing regimen used for the tablets (48, 32 and 16 h prior to the scheduled time 231
of admission for induction). 232
233
Release of ISMN from the VRs obeys root time (t0.5) kinetics, as evidenced by linear 234
cumulative release versus root-time graphs (Fig. 4B). Increasing the ISMN loading from 100 235
(F1) to 1000 mg (F3) significantly increased the ISMN release rate from 24.6 to 176.0 236
mg/day0.5 (Table 1). 237
238
Rings F3 and F4 both contained 1000 mg ISMN per ring, However, F3 contained ISMN 239
diluted with 30% lactose (as supplied), while F4 contained pure ISMN (i.e. no lactose). The 240
presence of the lactose diluent serves to significantly increase the rate of release of ISMN 241
from the rings (176.0 vs. 121.8 mg/day0.5; Table 1 and Fig. 4B). 242
243
Release of ISMN from reservoir and orifice-type rings is presented in Figs. 4C and 4D. Here, 244
daily ISMN release is relatively constant over the study period (Fig. 3C), at least compared to 245
the matrix-type rings (Fig. 3A), resulting in linear cumulative release vs. time profiles (Fig. 246
4D). Daily ISMN release from the reservoir ring containing a full-length ISMN-loaded core 247
(F6) decreased from 7.2 mg on Day 1 to 4.4 mg on Day 11. The half-core ring (F5) provided 248
Day 1 release of 3.7 mg and 2.2 mg on Day 11, approximately half the values for the full-core 249
ring (F6). Compared with Ring F6, the orifice-type ring (F7) had a relatively large amount of 250
ISMN release on Day 1 (10.3 vs. 7.2 mg) and a higher daily ISMN release rate (6.29 vs. 5.22 251
mg/day), clearly illustrating the impact of partly exposing the drug-loaded core to the SVF. 252
253
13
Unlike the matrix-type ring design, formulating the reservoir-type ring to contain pure ISMN 254
(F8; no lactose diluent) produced ISMN release rates identical to the reservoir ring containing 255
ISMN+lactose (F6) (Figs 4C and 4D). The water-soluble lactose is unable to modulate the 256
ISMN release from reservoir rings, since the lactose is contained only in the core of the device 257
and is not directly exposed to the SVF release medium. After 14 days, cumulative ISMN 258
release from the reservoir rings was 37.5, 74.2, 92.0 and 73.8 mg, F5–F8 respectively, 259
equivalent to 39.7%, 39.3%, 48.7% and 39.0% of the initial loadings (Table 1). 260
3.4. Release of MP from VRs 261
Ring F9 is the core component used to manufacture the orifice-type MP rings (F10–F13). Not 262
surprisingly, it displayed release behaviour typical of a matrix-type ring, including relatively 263
high Day 1 release (779 μg), declining amounts of MP released on subsequent days (233 μg 264
on Day 4 and only 26 μg on Day 11, Fig. 4E), and root-time kinetics (Fig. 4F). The quantities 265
of MP released during Day 1 and Day 4 were much higher than the safe clinical doses (25–266
200 μg) reported for vaginal administration of MP in IOL (Ambika et al., 2017; Calder et al., 267
2008; Chaudhuri et al., 2011; Frohn, 2002; Oboro and Tabowei, 2005). 268
269
When this F9 core was incorporated into a conventional reservoir-type ring, no release of MP 270
was observed. However, rings having either small circular orifices (F10, F11, F13) or larger 271
window-style orifices (F12) exposing an underlying full-length (F11 and F13) or a partial-272
length (F10 and F12) MP-loaded core showed significant MP release (Fig. 4G and 4H, Table 273
1). In general, the daily release profiles (Fig. 4G) do not show the burst-and-decline behaviour 274
of matrix-type rings (Fig. 4E); instead, greater constancy of release is observed, similar to a 275
conventional reservoir-type ring (Fig. 4C). Moreover, MP release is clearly shown to depend 276
14
upon the length of the core, the type of orifices (circular vs. elongated), and the number of 277
orifices. Inevitably, given that only part of the core in these rings is exposed to the SVF, the 278
release rates are reduced compared to ring F9. However, daily MP release rates tend to hover 279
around either 20 or 60 μg/day (Fig. 3G), conveniently straddling the dosing range currently 280
used in vaginal administration of MP for cervical ripening (Ambika et al., 2017; Calder et al., 281
2008; Chaudhuri et al., 2011; Frohn, 2002; Oboro and Tabowei, 2005). 282
283
Finally, ring formulation F13 – containing 5.4 mg MP in the core and 1209.8 mg ISMN in the 284
sheath (Table 1) – effectively demonstrates the utility of vaginal ring technology in offering 285
simultaneous and independent release of multiple cervical ripening agents over extended time 286
periods. For this combination drug ring, MP is released from the core of the device at an 287
almost constant rate of 60 μg/day (Figs. 4G and 4H), while the ISMN incorporated into the 288
sheath component provides Day 1 release of 295 mg followed by declining daily release on 289
each subsequent day and reaching 24 mg on Day 11 (Fig. 4I). After 14 days, the cumulative 290
amount of MP and ISMN released was 780 µg and 870 mg (Fig. 4J), respectively, equivalent 291
to 14.4% and 72.2% of the initial loadings, respectively (Table 1). 292
4. Discussion 293
In general, the silicone elastomer matrix-type rings are best suited to administration of daily 294
IMSN doses in the relatively high 1–200 mg range. The administered dose of ISMN was 295
readily modulated by adjusting the initial drug loading. Matrix rings provided an initial burst 296
release followed by declining release on subsequent days; as such, the release range would 297
need to carefully tailored for optimal clinical efficacy. However, constant low milligram-per-298
day release of ISMN was achieved with silicone elastomer reservoir rings, with the daily 299
15
release rate proportional to the length of the IMSN-loaded core. According to well-established 300
design principles for reservoir-type rings, the thickness of the rate-controlling membrane 301
could also be adjusted to further modulate release; for example, adjusting the membrane 302
thickness of the F5 and F6 rings to 0.78 mm (half of the current 1.55 mm) would result in a 303
two-fold increase in the daily ISMN release rate. Incorporating orifices in the membrane also 304
significantly increased the ISMN release rate and offered release kinetics intermediate 305
between conventional matrix and reservoir rings. 306
307
Much lower microgram-per-day doses of MP are required for IOL. Since conventional 308
reservoir-type VRs containing MP provided no release, we focused our attention on ring 309
designs including orifices in the membrane so as to expose, to varying extents, the MP-loaded 310
core to the release medium. By controlling the number of orifices, the size of orifices and the 311
length of the MP-loaded core, near-constant release rates in the range 20–60 µg/day could be 312
easily achieved. 313
314
This is the first study reporting VRs for sustained or controlled delivery cervical ripening 315
agents. The release rates of ISM and MP from VRs could be readily tailored by drug loading 316
and ring designs to meet the clinical requirements for IOL. This study is based on in vitro 317
testing of VRs, and therefore the release data may not correlate with performance in vivo. 318
However, for other VRs – most notably the dapivirine-releasing silicone elastomer VR for 319
prevention of sexual transmission of the human immunodeficiency virus (HIV) – in vitro 320
testing of dapivirine release using SVF correlated closely with in vivo release, based on 321
16
residual drug analysis content post-use (Baeten et al., 2016; Malcolm et al., 2016; McCoy et 322
al., 2017; Nel et al., 2016a). 323
324
VRs are already used successfully for estrogen replacement therapy and hormonal 325
contraception, and an antiretroviral-releasing VR will likely soon be available in Africa for 326
HIV prevention (Baeten et al., 2016; Nel et al., 2016a). The ring devices described in this 327
study are of similar size and fabricated from similar materials as other marketed vaginal ring 328
products (most notably Estring®, Femring® and the dapivirine-releasing ring). In general, VRs 329
are user-friendly, are easily inserted and removed by the woman, and are highly acceptable 330
(Mulders and Dieben, 2001; Novák et al., 2003). 331
332
As with other sustained/controlled release drug formulations, increased user acceptability and 333
compliance/adherence with VRs is often mooted as a potential advantage over more 334
conventional immediate release vaginal dosage forms (Malcolm et al., 2015). Previous studies 335
have reported high user acceptability and/or adherence of VRs for contraception and estrogen 336
replacement therapy (Ayton et al., 1996; Barentsen et al., 1997; Brache et al., 2000; Casper 337
and Petri, 1999; Dieben et al., 2002; Faundes et al., 1981; Nachtigall, 1995; Novák et al., 338
2003; Roumen et al., 2001; Roumen and Dieben, 1999; Stifani et al., 2018; Vartiainen et al., 339
1993; Weisberg et al., 1995). Yet, lower-than-expected adherence has been reported in late-340
stage clinical trials of the dapivirine ring, particularly among young women (Baeten et al., 341
2016; Montgomery et al., 2017; Nel et al., 2016b, 2016a; Spence et al., 2016). However, the 342
observed low adherence with the dapivirine may reflect various sociocultural issues 343
particularly pertinent to Sub-Saharan Africa and HIV infection (Montgomery et al., 2017). 344
17
The relatively short use regime intended for a VR for cervical ripening coupled with its use in 345
a managed primary care health setting should lead to high levels of user adherence. 346
347
The combination ISMN+MP ring described in this study is particular interesting, since 348
synergistic effects have previously been reported when administering the combination of 349
ISMN and MP intravaginally for cervical ripening (Abdellah et al., 2011; Elsokary et al., 350
2015; Soliman, 2013). 351
352
4. Conclusions 353
The results of this proof-of-concept study highlight the potential for development of long-354
acting sustained or controlled release drug delivery devices for low dose vaginal 355
administration of cervical ripening agents for IOL. The continuous dosing of small amounts 356
of these agents might be particularly useful in out-patient settings, reducing the time spent in 357
hospital, reducing health service costs, and offering increased user compliance compared to 358
periodic dosing regimens. The results strongly support progress to clinical testing. 359
360
Transparency declarations 361
The authors declare no conflicts of interest. 362
363
Acknowledgements 364
18
This study was funded through the UK Medical Research Council’s ‘Confidence in Concept’ 365
scheme (MC-PC-15035). 366
19
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Woolfson, A.D., Malcolm, R.K., Gallagher, R.J., 2003. Design of a silicone reservoir 659 intravaginal ring for the delivery of oxybutynin. J. Control. Release 91, 465–476. 660 https://doi.org/10.1016/S0168-3659(03)00277-3 661
Zhang, Y., Wang, J., Yu, Y., Xie, C., Xiao, M., Ren, L., 2015. Misoprostol versus 662 prostaglandin E2 gel for labor induction in premature rupture of membranes after 663 34weeks of pregnancy. Int. J. Gynecol. Obstet. 130, 214–218. 664 https://doi.org/10.1016/j.ijgo.2015.04.031 665
Zieman, M., Fong, S.K., Benowitz, N.L., Banskter, D., Darney, P.D., 1997. Absorption 666 kinetics of misoprostol with oral or vaginal administration. Obstet. Gynecol. 90, 88–92. 667 https://doi.org/10.1016/S0029-7844(97)00111-7 668
669
27
Table and figure captions 670
671
Table 1. Parameters for DDU-4320 VRs loaded with cervical ripening agents. Standard 672
deviation values were calculated based on four replicates. 673
674
Fig. 1. Cross-sectional views of (A) matrix rings, (B) reservoir rings and (C) orifice rings. D 675
– core ring mold assembly. E – orifice ring mold assembly, showing the protruding pins for 676
incorporation of orifices in the ring structure. 677
678
Fig. 2. Representative images of DDU-4320 VRs loaded with cervical ripening agents. F1-679
F4: matrix-type rings loaded with ISMN. F5-F6: reservoir-type or orifice-type rings loaded 680
with ISMN; F9-F13: matrix-type or orifice-type rings containing MP. 681
682
Fig. 3. A: DSC thermographs of the non-medicated silicone elastomer (SE), ISMN (70% w/w 683
dispersion in lactose), silicone elastomers loaded with ISMN, MP (1% w/w dispersion in 684
HPMC) and silicone elastomers loaded with MP. Each concentration of ISMN or MP in the 685
silicone elastomer is equivalent to the drug concentration in the ring formulation listed in the 686
brackets. B: melting enthalpy of the crystalline ISMN as a function of the mass fraction of 687
ISMN in silicone elastomer. The dotted line represents the result of the curve fitting. 688
689
Fig. 4. Daily release and cumulative release profiles for DDU-4320 VRs loaded with cervical 690
ripening agents over 14 days in SVF. A and B: daily release versus time and cumulative 691
release versus root time profiles of ISMN released from matrix-type rings loaded with 100 692
28
(F1), 500 (F2), 1000 (F3) and 1000 mg ISMN (without lactose, F4). C and D: daily release 693
and cumulative release of ISMN from Ring F5 (reservoir-type ring with half-length core), F6 694
(reservoir-type ring with full-length core), F7 (orifice-type ring with full-length core) and F8 695
(reservoir-type ring with full-length core, formulated with pure ISMN). The plot of F8 in 696
Graph B is not visible due to overlapping with the plot of F6. E and F: daily MP release versus 697
time plots and cumulative MP release versus root time plots for Ring F9. G and H: daily and 698
cumulative MP release versus time plots for Ring F10-13. I and J: daily ISMN release versus 699
time plots and cumulative ISMN release versus root time plots for Ring F13. 700